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Pharmacokinetics of dose-adjusted levonorgestrel emergency contraception combined with efavirenz-based antiretroviral therapy or rifampicin-containing tuberculosis regimens

Open AccessPublished:January 11, 2023DOI:https://doi.org/10.1016/j.contraception.2023.109951

      ABSTRACT

      Objectives

      To determine if double-dose levonorgestrel emergency contraception (EC) in combination with efavirenz or rifampicin, two drugs known to decrease levonorgestrel exposure, resulted in similar pharmacokinetics compared to standard-dose levonorgestrel EC without drug-drug interactions.

      Study Design

      We conducted a phase 2, open-label, multicenter, partially randomized, four parallel group trial in pre-menopausal females ≥16 years old without an indication for EC and not on hormonal contraception. Participants on dolutegravir-based antiretroviral therapy (ART) received levonorgestrel 1.5mg (control group); those on rifampicin-containing tuberculosis therapy received levonorgestrel 3mg; those on efavirenz-based ART were randomized 1:2 to levonorgestrel 1.5mg or 3mg. Plasma was collected through 48h post-dose to assess levonorgestrel pharmacokinetics. Area under the concentration-time curve (AUC) over 8 hours was the primary outcome. Levonorgestrel pharmacokinetic parameters were compared between groups using geometric mean ratios (GMR) with 90% confidence intervals.

      Results

      The median (Q1, Q3) age for all participants (n=118) was 34 (27, 41) years and BMI was 23.2 (20, 26.3) kg/m2. Participants receiving levonorgestrel 1.5mg plus efavirenz (n=17) had 50% lower AUC0-8h compared to the control group (n=32) [0.50 (0.40, 0.62)]. Participants receiving levonorgestrel 3mg had a similar AUC0-8h when receiving either efavirenz (n=35) [0.99 (0.81, 1.20)] or rifampicin (n=34) [1.16 (0.99, 1.36)] compared to control. Levonorgestrel 3mg resulted in similar or higher maximum concentration with either efavirenz [1.17 (0.96, 1.41)] or rifampicin [1.27 (1.09, 1.49)] compared to the control group.

      Conclusions

      Doubling the dose of levonorgestrel EC successfully increased levonorgestrel exposure over the first 8 hours in participants receiving either efavirenz-based ART or rifampicin-containing tuberculosis therapy.

      Key words

      1.0. INTRODUCTION

      Women account for over 50% of people living with HIV. In addition, tuberculosis (TB) remains one of the greatest threats to public health. For women living with either HIV or TB, unintended pregnancies are associated with poor maternal and neonatal outcomes [
      • Pillay T
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      • Adhikari M
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      Vertical transmission of Mycobacterium tuberculosis in KwaZulu Natal: impact of HIV-1 co-infection.
      ,
      • Sobhy S
      • Babiker Z
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      Maternal and perinatal mortality and morbidity associated with tuberculosis during pregnancy and the postpartum period: a systematic review and meta-analysis.
      ]. Emergency contraception (EC) is a safe and effective form of birth control when used intermittently after sex that could lead to pregnancy in the absence of other effective contraception [
      • Curtis KM
      • Tepper NK
      • Jatlaoui TC
      • Berry-Bibee E
      • Horton LG
      • Zapata LB
      • et al.
      U.S. Medical Eligibility Criteria for Contraceptive Use, 2016.
      ].
      Levonorgestrel EC is given as a single 1.5mg dose within 72 hours after unprotected sex that could lead to pregnancy. An inverse relationship between levonorgestrel pharmacokinetics (PK) and body mass index (BMI) has been reported [
      • Edelman AB
      • Cherala G
      • Blue SW
      • Erikson DW
      • Jensen JT.
      Impact of obesity on the pharmacokinetics of levonorgestrel-based emergency contraception: single and double dosing.
      ,
      • Natavio M
      • Stanczyk FZ
      • Molins EAG
      • Nelson A
      • Jusko WJ.
      Pharmacokinetics of the 1.5 mg levonorgestrel emergency contraceptive in women with normal, obese and extremely obese body mass index.
      ,
      • Praditpan P
      • Hamouie A
      • Basaraba CN
      • Nandakumar R
      • Cremers S
      • Davis AR
      • et al.
      Pharmacokinetics of levonorgestrel and ulipristal acetate emergency contraception in women with normal and obese body mass index.
      ]. Further, levonorgestrel is metabolized via the cytochrome P450 3A4 (CYP3A4) isoenzyme. Co-administration of medications that induce CYP3A4 decrease levonorgestrel concentrations. When combined with efavirenz or rifampicin in healthy volunteers, the levonorgestrel area under the concentration-time curve (AUC) was reduced by more than 50% [
      • Carten ML
      • Kiser JJ
      • Kwara A
      • Mawhinney S
      • Cu-Uvin S.
      Pharmacokinetic interactions between the hormonal emergency contraception, levonorgestrel (Plan B), and Efavirenz.
      ,
      • Wiesinger H
      • Klein S
      • Rottmann A
      • Nowotny B
      • Riecke K
      • Gashaw I
      • et al.
      The Effects of Weak and Strong CYP3A Induction by Rifampicin on the Pharmacokinetics of Five Progestins and Ethinylestradiol Compared to Midazolam.
      ]. Based on these data, European Medicines Authority and United Kingdom guidelines advise that women receiving CYP inducers receive double-dose levonorgestrel EC (3mg instead of 1.5mg) [

      European Medicines Agency. Emergency Contraceptives. October 2014. Available at: https://www.ema.europa.eu/en/medicines/human/referrals/emergency-contraceptives. Accessed 5 April 2022.

      ,

      Medicines and Healthcare products Regulatory Agency. Levonorgestrel-containing emergency hormonal contraception: advice on interactions with hepatic enzyme inducers and contraceptive efficacy. September 2016. Available at: https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers-and-contraceptive-efficacy. Accessed 5 April 2022.

      ]. However, there are no data to confirm this strategy restores levonorgestrel exposure in the presence of these drug-drug interactions (DDIs) without excess adverse events, nor are there data demonstrating the effectiveness of this strategy.
      AIDS Clinical Trial Group (ACTG) trial A5375 was designed to evaluate the PK and safety of dose-adjusted levonorgestrel EC in combination with efavirenz-based antiretroviral therapy (ART) or rifampicin-containing TB therapy. We hypothesized that doubling the dose of levonorgestrel EC in combination with either efavirenz or rifampicin would result in similar PK exposure and rate of adverse events compared with participants receiving standard-dose levonorgestrel EC in the absence of a DDI. We also evaluated the change in exposure that occurred when doubling the dose of levonorgestrel EC in participants receiving efavirenz-based ART.

      2.0. MATERIAL AND METHODS

      2.1 Study design

      A5375 was a phase 2, open-label, multicenter, partially randomized, four parallel group trial that enrolled participants at 18 ACTG sites in Botswana, Brazil, Kenya, Malawi, South Africa, Thailand, and the United States. Based on group assignment, levonorgestrel was administered as either 1.5mg or 3mg given once with food at entry. Participants with HIV who were receiving dolutegravir-based ART received levonorgestrel 1.5mg (control group). Participants with HIV who were taking efavirenz-based ART were randomized on a 1:2 basis to receive either levonorgestrel 1.5mg (efavirenz-levonorgestrel 1.5mg group) or 3mg (efavirenz-levonorgestrel 3mg group), utilizing centrally coordinated, computerized implementation of permuted blocks randomization (block size of 6) without stratification, and dynamic balancing within each institution (maximum allowed imbalance of 2). Participants without HIV in the continuation phase of rifampicin-containing TB therapy received levonorgestrel 3mg (rifampicin group). Because levonorgestrel PK is affected by body weight [
      • Edelman AB
      • Cherala G
      • Blue SW
      • Erikson DW
      • Jensen JT.
      Impact of obesity on the pharmacokinetics of levonorgestrel-based emergency contraception: single and double dosing.
      ,
      • Natavio M
      • Stanczyk FZ
      • Molins EAG
      • Nelson A
      • Jusko WJ.
      Pharmacokinetics of the 1.5 mg levonorgestrel emergency contraceptive in women with normal, obese and extremely obese body mass index.
      ,
      • Praditpan P
      • Hamouie A
      • Basaraba CN
      • Nandakumar R
      • Cremers S
      • Davis AR
      • et al.
      Pharmacokinetics of levonorgestrel and ulipristal acetate emergency contraception in women with normal and obese body mass index.
      ], we limited enrollment of participants with a body mass index (BMI) ≥30 kg/m2 to no more than 18% per group.
      Intensive PK sampling occurred over 48 hours around the levonorgestrel dose. The visit was not timed according to the menstrual cycle. Adverse events were assessed at each in-person visit, and by phone 7, 14, and 28 days after the levonorgestrel dose. The study was conducted in accordance with the Declaration of Helsinki and registered at ClinicalTrials.gov (NCT03819114). The study was approved by an institutional review board at each study site and written informed consent was obtained from each participant.

      2.2 Participants

      Detailed inclusion and exclusion criteria are provided in Supplementary Material. Participants were non-pregnant volunteers who did not require EC at entry (i.e., no unprotected sex that could lead to pregnancy in the previous 14 days). Participants were required to be at least 16 years of age, post-menarchal, pre-menopausal, assigned female sex at birth, without a history of bilateral oophorectomy or hysterectomy, and not breastfeeding an infant under six months of age. All participants agreed to use a non-hormonal method of contraception during the study and could not have recent exposure to hormones or drugs known to interact with levonorgestrel based on self-report.
      Participants with HIV could not be on treatment for active TB and were taking either efavirenz 600mg daily or dolutegravir 50mg daily plus two nucleoside-reverse transcriptase inhibitors for at least 30 days prior to enrollment. Participants with TB had a recent negative HIV test and were receiving daily rifampicin plus isoniazid, with or without ethambutol. Rifampicin was dosed by weight (10mg/kg/day) in accordance with local standard of care.

      2.3 PK assessment and analyses

      At the entry visit, blood samples were collected before the levonorgestrel dose, and then 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48-hours post-dose. Participants were allowed to leave the clinical research site after 8-hours and returned for 24- and 48-hour sampling. Participants who reported missing an ART or rifampicin dose in previous three days had the visit rescheduled. From each participant, one sample was identified for additional analysis of efavirenz, (12-20h post-dose), dolutegravir, (20-28h post-dose), or rifampicin and desacetyl-rifampicin (1-16h post-dose). These timeframes were selected to correspond with previously defined PK-pharmacodynamic relationships for efavirenz and dolutegravir [
      • Marzolini C
      • Telenti A
      • Decosterd LA
      • Greub G
      • Biollaz J
      • Buclin T.
      Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients.
      ,
      • Podany AT
      • Scarsi KK
      • Pham MM
      • Fletcher CV.
      Comparative Clinical Pharmacokinetics and Pharmacodynamics of HIV-1 Integrase Strand Transfer Inhibitors: An Updated Review.
      ], and the most recent sample post-reported dose for rifampicin, because of its short half-life. Plasma was separated within one hour of blood collection and stored at ≤-70°C until analysis. Drug concentrations were quantified by validated, quality-controlled, liquid chromatography-tandem mass spectroscopy methods [
      • Cirrincione LR
      • Penchala SD
      • Scarsi KK
      • Podany AT
      • Winchester LC
      • Back DJ
      • et al.
      Development, validation and utilization of a highly sensitive LC-MS/MS method for quantification of levonorgestrel released from a subdermal implant in human plasma.
      ,
      • Fletcher CV
      • Brundage RC
      • Fenton T
      • Alvero CG
      • Powell C
      • Mofenson LM
      • et al.
      Pharmacokinetics and pharmacodynamics of efavirenz and nelfinavir in HIV-infected children participating in an area-under-the-curve controlled trial.
      ,
      • Winchester LC
      • Podany AT
      • Baldwin JS
      • Robbins BL
      • Fletcher CV.
      Determination of the rifamycin antibiotics rifabutin, rifampin, rifapentine and their major metabolites in human plasma via simultaneous extraction coupled with LC/MS/MS.
      ]. The coefficient of variation of each analyte was less than 15%, and the assays met Food and Drug Administration guidance on bioanalytical method validation criteria [

      US Food and Drug Administration. Bioanalytical Method Validation: Guidance for Industry. Available at: https://www.fda.gov/media/70858/download. Accessed 5 April 2022.

      ].
      Non-compartmental analysis of levonorgestrel was performed with WinNonLin (Certara®, Princeton, NJ, USA) software using the linear up/log down trapezoidal rule to estimate AUCs, apparent oral clearance (Cl/F), apparent volume of distribution (Vd/F), and elimination half-life (T1/2). The maximum concentration (Cmax), time to Cmax (Tmax), and last concentration (Clast) were directly observed. Any concentrations below the limit of quantification and occurring post-dose were set to half the lower limit of quantification. All levonorgestrel concentrations were used to calculate individual PK parameters with no additional adjustments or exclusions. To avoid potential loss of power or introduction of bias due to participants who did not return for the 24- and 48-hour sampling, the primary outcome was specified a priori as AUC from 0-8 hours; the AUCs from 0-24h, 0-48h, and to infinity were calculated to provide a comparison with published levonorgestrel EC evaluations.

      2.4 Safety assessments

      We evaluated safety in all participants and reported adverse events by dose received: 1.5mg versus 3mg. Participants had a targeted physical exam at entry and when indicated. Participants were asked about their typical menstrual cycle at study entry (reflecting the past 6 months) and again at each study visit, including their perception of the usual frequency of cycles, duration of bleeding, and spotting. Study related menstrual changes had to be either new in onset or aggravated in severity or frequency from baseline. Severity of adverse events were assessed using the Division of AIDS Adverse Event Grading Table and the Female Genital Grading Table for Use in Microbicide Studies [

      Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. Addendum 1: Female Genital Grading Table for Use in Microbicide Studies. December 2004. Available at: https://rsc.niaid.nih.gov/sites/default/files/addendum-1-female-genital-grading-table-v1-nov-2007.pdf. Accessed 5 April 2022.

      ,

      Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events. July 2017. Available at: https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf. Accessed 5 April 2022.

      ]. All adverse events were assessed by site investigators; only the following required reporting to case report forms: pregnancy, serious adverse events [

      Manual for Expedited Reporting of Adverse Events to DAIDS. Version 2.0. January 2010. Available at: https://rsc.niaid.nih.gov/sites/default/files/manual-exped-aes-v2_0.pdf. Accessed 5 April 2022.

      ], Grade ≥3 adverse event, or Grade ≥2 nausea, diarrhea, or menstrual abnormalities potentially related to levonorgestrel.

      2.5 Statistical analysis

      For primary objectives, the target sample size was 30 in the control, efavirenz-levonorgestrel 3mg, and rifampicin groups. Assumptions included the levonorgestrel AUC0-8hr coefficient of variation of 0.45, and 10% significance, corresponding to inverting two 5% one-sided tests (TOST). Assuming equivalence, there was 88% statistical power for declaring similarity in AUC0-8hr between either 3mg levonorgestrel group versus control, using reference interval of (0.7, 1.43) [
      • Begley R
      • Anderson K
      • Watkins TR
      • Weng W
      • Ampaw L
      • Qin A
      • et al.
      Lack of Drug-Drug Interaction Between Filgotinib, a Selective JAK1 Inhibitor, and Oral Hormonal Contraceptives Levonorgestrel/Ethinyl Estradiol in Healthy Volunteers.
      ,
      • Majeed SR
      • West S
      • Ling KH
      • Das M
      • Kearney BP.
      Confirmation of the drug-drug interaction potential between cobicistat-boosted antiretroviral regimens and hormonal contraceptives.
      ]. Target sample size of 15 participants in the efavirenz-levonorgestrel 1.5mg group, provided 80% statistical power that the true 1.5mg versus 3mg levonorgestrel AUC0-8hr geometric mean ratio (GMR) was ≤0.67.
      Inclusion in the primary PK analysis required sufficient samples to calculate levonorgestrel AUC0-8hr. In a PK sensitivity analysis, we excluded participants with inadequate companion drug levels: efavirenz <650 ng/mL (the lower 95% prediction bound 20 hours post dose), dolutegravir <398 ng/mL (lower 95% bound of the trough), or rifampicin below the limit of quantitation (<75 ng/mL for rifampicin, <37.5 ng/mL for desacetyl-rifampicin) [
      • Csajka C
      • Marzolini C
      • Fattinger K
      • Decosterd LA
      • Fellay J
      • Telenti A
      • et al.
      Population pharmacokinetics and effects of efavirenz in patients with human immunodeficiency virus infection.
      ,
      • Min S
      • Sloan L
      • DeJesus E
      • Hawkins T
      • McCurdy L
      • Song I
      • et al.
      Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults.
      ].
      The 90% confidence interval (CI) on the GMR was calculated using pooled variance of the difference and log-transformation of PK parameters; CI of 90% matches TOST each at 5%. The anti-log of GMRs and confidence bounds are reported. Since weight is prognostic for levonorgestrel exposure [
      • Edelman AB
      • Cherala G
      • Blue SW
      • Erikson DW
      • Jensen JT.
      Impact of obesity on the pharmacokinetics of levonorgestrel-based emergency contraception: single and double dosing.
      ,
      • Natavio M
      • Stanczyk FZ
      • Molins EAG
      • Nelson A
      • Jusko WJ.
      Pharmacokinetics of the 1.5 mg levonorgestrel emergency contraceptive in women with normal, obese and extremely obese body mass index.
      ,
      • Praditpan P
      • Hamouie A
      • Basaraba CN
      • Nandakumar R
      • Cremers S
      • Davis AR
      • et al.
      Pharmacokinetics of levonorgestrel and ulipristal acetate emergency contraception in women with normal and obese body mass index.
      ], GMRs were adjusted for BMI via inclusion in a linear model.
      A historical group verified absence of DDI between levonorgestrel and dolutegravir-based ART [
      • Praditpan P
      • Hamouie A
      • Basaraba CN
      • Nandakumar R
      • Cremers S
      • Davis AR
      • et al.
      Pharmacokinetics of levonorgestrel and ulipristal acetate emergency contraception in women with normal and obese body mass index.
      ]. Within BMI subgroups, AUC0-24h GMRs and 90% CIs (using Satterthwaite standard error) reflected control versus historical group comparisons.
      Imbalances between non-randomized groups in a priori selected baseline characteristics were tested using Fisher's exact tests and Wilcoxon Rank Sum tests, using 5% significance. Statistical analyses used SAS (v9.4, SAS Institute, Cary, NC).

      3.0. RESULTS

      We enrolled 122 participants between May 2019 and November 2020; four did not meet criteria for the primary PK analysis (Figure 1), leaving 32 participants in the control group, 17 in the efavirenz-levonorgestrel 1.5mg group, 35 in the efavirenz-levonorgestrel 3mg group, and 34 in the rifampicin group. Baseline characteristics are described in Table 1. The median BMI across all groups was 23.2 kg/m2. The country of enrollment and participant race/ethnicity differed by group; age and BMI was statistically different between the rifampicin and control groups.
      Figure 1
      Figure 1Participant disposition. Primary PK analysis set includes all participants included in the analysis. PK sensitivity analysis set excludes participants with suboptimal dolutegravir, efavirenz, or rifampicin concentrations.
      Abbreviations: ART, antiretroviral therapy; DTG, dolutegravir; EFV, efavirenz; LNG, levonorgestrel; PK, pharmacokinetic; RIF, rifampicin.
      Table 1Baseline demographics and clinical characteristics.
      CharacteristicsControl group: LNG 1.5mg + DTG-based ART (n=32)EFV-LNG 1.5mg group: LNG 1.5mg + EFV-based ART (n=17)EFV-LNG 3mg group: LNG 3mg + EFV-based ART (n=35)RIF group: LNG 3mg + RIF-containing TB therapy (n=34)Total (n=118)
      Age in years, median (Q1, Q3)
      Comparisons of age among non-randomized groups: EFV-LNG 1.5mg vs control (p=0.008); EFV-LNG 3mg vs control (p=0.4); RIF vs control (0.002) [p-values from Wilcoxon Rank Sum Tests]
      34 (29, 40)42 (35, 45)36 (29, 42)25 (21, 35)34 (27, 41)
      Cis-gender females, n (%)32 (100%)17 (100%)35 (100%)34 (100%)118 (100%)
      Country, n (%)
      Comparisons of country among non-randomized groups: EFV-LNG 1.5mg vs control; EFV-LNG 3mg vs control; RIF vs control all p < 0.001 [p-values from Fisher's exact Tests]
      Botswana0 (0%)0 (0%)0 (0%)2 (6%)2 (2%)
      Brazil4 (13%)1 (6%)3 (9%)2 (6%)10 (8%)
      Kenya0 (0%)0 (0%)0 (0%)4 (12%)4 (3%)
      Malawi10 (31%)0 (0%)0 (0%)6 (18%)16 (14%)
      South Africa2 (6%)7 (41%)12 (34%)18 (53%)39 (33%)
      Thailand2 (6%)9 (53%)20 (57%)2 (6%)33 (28%)
      United States14 (44%)0 (0%)0 (0%)0 (0%)14 (12%)
      Race/Ethnicity, n (%)
      Comparisons of race/ethnicity among non-randomized groups: EFV-LNG 1.5mg vs control (p=0.002); EFV-LNG 3mg vs control (p<0.001.); RIF vs control (0.56) [p-values from Fisher's exact Tests]
      Asian2 (6%)9 (53%)20 (57%)2 (6%)33 (28%)
      Black24 (75%)7 (41%)12 (34%)30 (88%)73 (62%)
      Multiple races1 (3%)0 (0%)0 (0%)0 (0%)1 (1%)
      White1 (3%)0 (0%)0 (0%)0 (0%)1 (1%)
      Hispanic or Latino4 (13%)1 (6%)3 (9%)2 (6%010 (8%)
      Body weight, median (Q1, Q3), kg62.2 (54.5, 74.3)52.3 (46.5, 68.9)58.5 (50.3, 74.0)54.6 (48.0, 61.9)58.4 (50.2, 68.9)
      BMI, median (Q1, Q3), kg/m2
      Comparisons of BMI among non-randomized groups: EFV-LNG 1.5mg vs control (p=0.06); EFV-LNG 3mg vs control (p=0.31); RIF vs control (0.01) [p-values from Wilcoxon Rank Sum Tests]
      25.3 (21.6, 28.1)20.3 (18.3, 26.0)23.5 (20.5, 26.6)21.5 (19.7, 24.5)23.2 (20.0, 26.3)
      BMI category, n (%)
      Comparisons of BMI category among non-randomized groups: EFV-LNG 1.5mg vs control (p=0.14); EFV-LNG 3mg vs control (p=0.26); RIF vs control (0.048) [p-values from Fisher's exact Tests]
      Underweight <18.5 kg/m23 (9%)5 (29%)2 (6%)7 (21%)17 (14%)
      Normal weight 18.5 – 24.9 kg/m212 (38%)7 (41%)21 (60%)20 (59%)60 (51%)
      Overweight 25.0 – 29.9 kg/m212 (38%)2 (12%)7 (20%)4 (12%)25 (21%)
      Obese ≥30 kg/m25 (16%)3 (18%)5 (14%)3 (9%)16 (14%)
      Time on efavirenz, dolutegravir, or rifampicin (months), median (Q1, Q3)12.4 (3.0, 27.0)38.8 (32.3, 69.7)32.4 (23.7, 58.9)3.8 (3.2, 5.1)
      HIV group characteristicsTotal (n=84)
      HIV-1 RNA <40 copies/mL, n (%)27 (84%)14 (82%)35 (100%)76 (90%)
      HIV-1 RNA, median (Q1, Q3), copies/mL
      Comparisons of age among non-randomized groups: EFV-LNG 1.5mg vs control (p=0.008); EFV-LNG 3mg vs control (p=0.4); RIF vs control (0.002) [p-values from Wilcoxon Rank Sum Tests]
      ,
      Among those with HIV-1 RNA ≥40 copies/mL
      314 (223, 6238) (n=5)642 (163, 770) (n=3)478 (193, 3504) (n=8)
      CD4+, median (Q1, Q3), cells/mm3599 (389, 864)548 (426, 611)676 (520, 834)629 (427, 815)
      Co-administered ARV medications, n (%)
      Lamivudine/tenofovir DF15 (47%)1 (6%)2 (6%)
      Abacavir/lamivudine6 (19%)0 (0%)1 (3%)
      Emtricitabine/tenofovir DF3 (9%)16 (94%)32 (91%)
      Emtricitabine/tenofovir AF8 (25%)0 (0%)0 (0%)
      Abbreviations: AF, alafenamide; ARV, antiretroviral; ART, antiretroviral therapy; BMI, body mass index; DF, disoproxil fumarate; DTG, dolutegravir; EFV, efavirenz; LNG, levonorgestrel; TB, tuberculosis
      a Comparisons of age among non-randomized groups: EFV-LNG 1.5mg vs control (p=0.008); EFV-LNG 3mg vs control (p=0.4); RIF vs control (0.002) [p-values from Wilcoxon Rank Sum Tests]
      b Comparisons of country among non-randomized groups: EFV-LNG 1.5mg vs control; EFV-LNG 3mg vs control; RIF vs control all p < 0.001 [p-values from Fisher's exact Tests]
      c Comparisons of race/ethnicity among non-randomized groups: EFV-LNG 1.5mg vs control (p=0.002); EFV-LNG 3mg vs control (p<0.001.); RIF vs control (0.56) [p-values from Fisher's exact Tests]
      d Comparisons of BMI among non-randomized groups: EFV-LNG 1.5mg vs control (p=0.06); EFV-LNG 3mg vs control (p=0.31); RIF vs control (0.01) [p-values from Wilcoxon Rank Sum Tests]
      e Comparisons of BMI category among non-randomized groups: EFV-LNG 1.5mg vs control (p=0.14); EFV-LNG 3mg vs control (p=0.26); RIF vs control (0.048) [p-values from Fisher's exact Tests]
      f Among those with HIV-1 RNA ≥40 copies/mL

      3.1 Pharmacokinetic outcomes

      Using our designated historical comparator [
      • Praditpan P
      • Hamouie A
      • Basaraba CN
      • Nandakumar R
      • Cremers S
      • Davis AR
      • et al.
      Pharmacokinetics of levonorgestrel and ulipristal acetate emergency contraception in women with normal and obese body mass index.
      ], we first confirmed there was no evidence of a DDI between dolutegravir-based ART and levonorgestrel (Supplementary Table 1). The levonorgestrel AUC0-24h were similar among both normal BMI [GMR 0.97, 90% CI (0.73, 1.29)] and obese BMI [0.81 (0.58, 1.14)], thus affirming participants receiving dolutegravir-based ART were an appropriate control group.
      To assess the primary objectives of evaluating the double-dose groups compared to standard dose in the absence of a DDI, we compared each levonorgestrel 3mg group to the control group. In the efavirenz-levonorgestrel 3mg group, Cmax and AUC0-8h were similar to the control group (Figure 2C; Table 2). The levonorgestrel half-life was 46% shorter (median: 11.8 hours vs. 24.0 hours), resulting in 76% lower Clast, 30% lower AUC0-24h, and 42% lower AUC0-48h compared to control. In the rifampicin group, the AUCs over the first 8 and 24 hours were similar to the control group (Figure 2D; Table 2). The Cmax was 27% higher, while the half-life was 57% shorter in the rifampicin group, resulting in 82% lower Clast and 21% lower AUC48h. While the primary results were adjusted for BMI, unadjusted results are presented in Supplemental Table 3.
      Figure 2
      Figure 2Levonorgestrel concentration-time curve (median, 25% and 75% quartile) in plasma over 48 hours after a single dose of emergency contraception. a illustrates the control group (solid line, triangle) compared to efavirenz-levonorgestrel 1.5mg group (dotted-line, squares). b illustrates the efavirenz-levonorgestrel 1.5mg group (dotted-line, squares) and the efavirenz-levonorgestrel 3mg group (dashed line, circles). c illustrates the control group (solid line, triangle) compared to the efavirenz-levonorgestrel 3mg group (dashed line, circles). d illustrates control group (solid line, triangle) compared to the rifampicin group (dashed line, squares). The control group participants were on dolutegravir-based ART and received levonorgestrel 1.5mg. The efavirenz-levonorgestrel 1.5mg group participants were on efavirenz-based ART and received levonorgestrel 1.5mg. The efavirenz-levonorgestrel 3mg group participants were on efavirenz-based ART and received levonorgestrel 3mg. The rifampicin group participants were on rifampicin-containing tuberculosis therapy in the continuation phase and received levonorgestrel 3mg. Levonorgestrel was administered as a single dose with food at time 0.
      Table 2Levonorgestrel plasma pharmacokinetic parameters over 48-hours after a single dose of emergency contraception.
      Median (Q1, Q3)GMR (90% Confidence Interval)

      Adjusted for BMI
      Pharmacokinetic parametersControl group: LNG 1.5mg + DTG-based ART (n=32)EFV-LNG 1.5mg group: LNG 1.5mg + EFV-based ART (n=17)
      See supplementary material for GMR and 90% confidence interval comparisons with the standard dose efavirenz group and the control group.
      EFV-LNG 3mg group: LNG 3mg + EFV-based ART (n=35)RIF group: LNG 3mg + RIF-containing TB therapy (n=34)EFV-LNG 3mg group vs. Control groupRIF group vs. Control group
      Cmax (ng/mL)18.7 (14.1, 26.2)15.1 (11.2, 24.0)24.9 (16.2, 29.6)28.0 (23.0, 39.6)1.10 (0.93, 1.31)1.27 (1.09, 1.49)
      Tmax (h)2.0 (1.5, 3.0)1.5 (1.5, 2.1)2.0 (1.5, 3.0)2.0 (1.5, 3.0)
      Clast (ng/mL)
      All Clast concentrations were drawn 48 hours after the levonorgestrel dose, except one participant in the control group, which was drawn 24 hours post-dose.
      2.8 (1.5, 3.7)0.3 (0.2, 0.4)0.6 (0.3, 1.1)0.5 (0.2, 1.0)0.24 (0.17, 0.34)0.18 (0.11, 0.27)
      Vd/F (L)169.1 (93.8, 215.2)276.7 (118.3, 411.8)294.9 (208.7, 489.5)156.3 (105.3, 247.2)2.28 (1.87, 2.78)1.36 (1.13, 1.65)
      Cl/F (L/h)4.4 (2.9, 6.6)12.6 (10.4, 21.1)15.2 (12.6, 27.7)12.1 (9.0, 16.3)4.22 (3.35, 5.33)3.18 (2.53, 4.00)
      T1/2 (h)24.0 (20.0, 28.0)12.1 (8.6, 13.7)11.8 (10.6, 13.8)9.0 (6.7, 11.9)0.54 (0.49, 0.60)0.43 (0.39, 0.48)
      AUC0-8h (h*ng/mL)
      AUC0-8h was the primary outcome.
      80.5 (66.6, 125.0)52.1 (36.7, 88.3)102.1 (64.5, 114.8)124.4 (87.1, 168.8)0.92 (0.78, 1.10)1.16 (0.99, 1.36)
      AUC0-24h (h*ng/mL)157.6 (132.3, 282.3)81.6 (56.1, 128.5)153.4 (100.1, 190.5)213.7 (148.6, 283.2)0.70 (0.57, 0.85)0.96 (0.79, 1.17)
      AUC0-48h (h*ng/mL)224.8 (178.3, 400.9)99.0 (66.4, 141.3)180.3 (106.9, 216.8)242.7 (181.6, 322.0)0.58 (0.47, 0.72)0.79 (0.63, 0.97)
      AUCinf (h*ng/mL)345.8 (227.8, 518.7)118.7 (71.2, 143.7)196.8 (108.5, 238.2)249.0 (183.9, 333.0)0.47 (0.38, 0.60)0.63 (0.50, 0.79)
      Abbreviations: AUC, area under the concentration-time curve; BMI, body mass index; Clast, last observed concentration; Cl/F, apparent clearance; Cmax, maximum concentration; DTG, dolutegravir; EFV, efavirenz; GMR, geometric mean ratio; LNG, levonorgestrel; RIF, rifampicin; Tmax, time of maximum concentration; Vd/F, apparent volume of distribution; T1/2, apparent half-life.
      a See supplementary material for GMR and 90% confidence interval comparisons with the standard dose efavirenz group and the control group.
      b All Clast concentrations were drawn 48 hours after the levonorgestrel dose, except one participant in the control group, which was drawn 24 hours post-dose.
      c AUC0-8h was the primary outcome.
      Compared to the control group, the efavirenz-levonorgestrel 1.5mg group had 50% lower AUC0-8h [0.50 (0.40, 0.62)] (Figure 2A; Supplementary Table 2). The half-life was nearly two-fold shorter, which resulted in 64-70% lower exposure over 24 and 48 hours compared to the control group. Comparing levonorgestrel 1.5mg vs. 3mg in participants receiving efavirenz-based ART (Figure 2B; Supplementary Table 2), those taking levonorgestrel 3mg had higher AUC0-8h [1.81 (1.42, 2.30)], which remained 88-90% higher over 24- and 48-hours post-dose. The Cmax was 61% higher in the 3mg vs. 1.5mg efavirenz groups [24.9 (16.2, 29.6) vs. 15.1 (11.2, 24) ng/mL] and Clast was 126% higher [0.61 (1.45, 3.67) vs. 0.32 (0.2, 0.38) ng/mL]. Other PK parameters were similar between the two efavirenz groups.
      In the PK sensitivity analyses, nine participants with inadequate companion drug concentrations were excluded, four in the control group, one in the efavirenz-levonorgestrel 3mg group, and four in the rifampicin group. Results were similar to the primary analyses (Supplementary Tables 2 and 3).

      3.2 Safety outcomes

      Of the 122 participants enrolled, two participants (4%) receiving levonorgestrel 1.5mg and two participants (3%) receiving levonorgestrel 3mg experienced reportable adverse events. In the 1.5mg dosing groups, one participant had Grade 2 nausea after the levonorgestrel dose on day 0 and one participant experienced Grade 2 heavy menstrual bleeding on day 26. In the 3mg dosing groups, one participant had Grade 2 nausea on day 0, and another participant had Grade 2 nausea on day 0, Grade 2 intermenstrual bleeding on day 4, and Grade 3 headache and menstrual discomfort in the final week of follow-up. No pregnancies were reported during follow-up.

      4.0. DISCUSSION

      This trial demonstrated that adjusting levonorgestrel EC from 1.5mg to 3mg in participants receiving either efavirenz-based ART or rifampicin-containing TB therapy resulted in similar levonorgestrel exposure in the first 8 hours post-dose. Both efavirenz and rifampicin induced the metabolism of levonorgestrel, resulting in a shorter half-life and lower levonorgestrel exposure at the end of the 48-hour PK sampling interval. Although there are no data directly evaluating the PK:pharmacodynamic relationship of levonorgestrel EC, an adequate Cmax is desired to prevent or delay ovulation [
      • Edelman AB
      • Cherala G
      • Blue SW
      • Erikson DW
      • Jensen JT.
      Impact of obesity on the pharmacokinetics of levonorgestrel-based emergency contraception: single and double dosing.
      ]. Doubling the dose of levonorgestrel resulted in similar, or higher, Cmax in both 3mg study groups. While these data support guideline recommendations to increase the dose of levonorgestrel to improve PK, without increasing adverse effects of levonorgestrel in people requiring EC plus efavirenz or rifampicin [

      European Medicines Agency. Emergency Contraceptives. October 2014. Available at: https://www.ema.europa.eu/en/medicines/human/referrals/emergency-contraceptives. Accessed 5 April 2022.

      ,

      Medicines and Healthcare products Regulatory Agency. Levonorgestrel-containing emergency hormonal contraception: advice on interactions with hepatic enzyme inducers and contraceptive efficacy. September 2016. Available at: https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-hormonal-contraception-advice-on-interactions-with-hepatic-enzyme-inducers-and-contraceptive-efficacy. Accessed 5 April 2022.

      ], it is unknown if this correction of exposure over the first 8 hours is sufficient to maintain EC effectiveness.
      Consistent with prior evaluations of standard dose levonorgestrel with efavirenz in healthy volunteers [
      • Carten ML
      • Kiser JJ
      • Kwara A
      • Mawhinney S
      • Cu-Uvin S.
      Pharmacokinetic interactions between the hormonal emergency contraception, levonorgestrel (Plan B), and Efavirenz.
      ], the administration of levonorgestrel 1.5mg plus efavirenz-based ART resulted in 50% lower exposure over 8 hours compared to the control group. Over 48 hours, the AUC was 70% lower, and the Clast was 90% lower than the control group. This reflects a shorter half-life of levonorgestrel, consistent with efavirenz inducing levonorgestrel metabolism. Levonorgestrel exposure was not proportionally increased when participants on efavirenz received double-dose levonorgestrel. While the Clast was two-fold higher in the 3mg vs 1.5mg efavirenz-levonorgestrel groups, the Cmax and AUCs were only 51-80% higher. These findings are consistent with levonorgestrel contraceptive implants in combination with efavirenz-based ART, where proportionally higher plasma exposure was not observed with double-dose levonorgestrel implants over 48 weeks [
      • Scarsi KK
      • Cirrincione L
      • Nakalema S
      • Darin K
      • Musinguzi I
      • Byakika-Kibwika P
      • et al.
      Double-dose levonorgestrel implant does not fully overcome interaction with efavirenz.
      ].
      In contrast, Edelman and colleagues evaluated dose escalation to overcome decreased levonorgestrel exposure in obesity and reported similar Cmax and AUC over 2.5 hours post-dose in obese individuals receiving levonorgestrel 3mg compared to individuals with normal BMI receiving standard dose [
      • Edelman AB
      • Cherala G
      • Blue SW
      • Erikson DW
      • Jensen JT.
      Impact of obesity on the pharmacokinetics of levonorgestrel-based emergency contraception: single and double dosing.
      ], consistent with our findings over 8 hours post-dose. In a follow-up, randomized, controlled trial, Edelman and colleagues found no difference in ovulation delay in obese individuals despite dose escalation (follicle rupture: 1.5mg, 17/35 (48.6%); 3mg, 11/35, (31.4%), p=0.14], nor in the time to follicle rupture (p=0.21) [
      • Edelman AB
      • Hennebold JD
      • Bond K
      • Lim JY
      • Cherala G
      • Archer DF
      • et al.
      Double Dosing Levonorgestrel-Based Emergency Contraception for Individuals With Obesity: A Randomized Controlled Trial.
      ]. The authors propose that levonorgestrel PK:pharmacodynamic changes may be due to changes in protein binding or differences in the hypothalamus-pituitary-ovulation relationship related to obesity. While it is unclear if these results would be similar in the setting of a DDI which enhances drug clearance rather than physiologic changes related to obesity, the findings highlight that alternative options for EC may be preferred. Unfortunately, the alternative oral EC, ulipristal, is also metabolized by CYP3A4 enzymes, resulting in similar DDI concerns, and the copper intrauterine device is not consistently available or accessible in areas where HIV and TB are most prevalent.
      Pharmacogenetics may contribute to the extent of the DDI observed. Prior evaluations of progestin DDIs with efavirenz found that individuals who have CYP2B6 polymorphisms, which result in slower efavirenz metabolism (thus higher overall efavirenz concentrations), had lower progestin concentrations when combined with efavirenz than those without these polymorphisms [
      • Haas DW
      • Cramer YS
      • Godfrey C
      • Rosenkranz SL
      • Aweeka F
      • Berzins B
      • et al.
      Pharmacogenetic interactions between antiretroviral drugs and vaginally administered hormonal contraceptives.
      ,
      • Neary M
      • Chappell CA
      • Scarsi KK
      • Nakalema S
      • Matovu J
      • Achilles SL
      • et al.
      Effect of patient genetics on etonogestrel pharmacokinetics when combined with efavirenz or nevirapine ART.
      ,
      • Neary M
      • Lamorde M
      • Olagunju A
      • Darin KM
      • Merry C
      • Byakika-Kibwika P
      • et al.
      The Effect of Gene Variants on Levonorgestrel Pharmacokinetics When Combined With Antiretroviral Therapy Containing Efavirenz or Nevirapine.
      ]. In addition, all participants in the rifampicin group were receiving isoniazid. Recent data suggest individuals who are NAT2 slow acetylators have higher concentrations of isoniazid, a mechanistic CYP inhibitor, resulting in higher concentrations of CYP3A4 metabolized medications [
      • Haas DW
      • Podany AT
      • Bao Y
      • Swindells S
      • Chaisson RE
      • Mwelase N
      • et al.
      Pharmacogenetic interactions of rifapentine plus isoniazid with efavirenz or nevirapine.
      ]. Planned future work will evaluate if pharmacogenetic characteristics influenced the levonorgestrel exposure in trial participants.
      This trial has limitations to consider when interpreting the findings. First, participants did not require EC for prevention of pregnancy at entry and was not designed to evaluate contraceptive effectiveness. Second, we observed differences in age, BMI, country of enrollment, and race between groups, and there is the potential for residual confounding due to lack of randomization between some groups. While BMI was adjusted for in our comparisons, we did not adjust for other differences between groups. Without daily menstrual cycle diaries, we may not have adequately captured menstrual cycle abnormalities. Finally, if adherence to efavirenz or rifampicin were suboptimal prior to entry, we may have observed higher levonorgestrel exposure in the 3mg arms, which may overestimate the effect of levonorgestrel dose-adjustment compared to the control group. Reassuringly, the results of the PK sensitivity analysis were similar to our primary estimates.
      Unintended pregnancy rates are high worldwide. This is especially true in areas of limited resources where both HIV and TB infections are a significant public health burden, and women are less empowered to control their reproductive health. Gender based violence against women, including sexual violence, is linked to HIV acquisition, and may be associated with poorer treatment outcomes [
      • Leddy AM
      • Weiss E
      • Yam E
      • Pulerwitz J.
      Gender-based violence and engagement in biomedical HIV prevention, care and treatment: a scoping review.
      ,
      • Li Y
      • Marshall CM
      • Rees HC
      • Nunez A
      • Ezeanolue EE
      • Ehiri JE.
      Intimate partner violence and HIV infection among women: a systematic review and meta-analysis.
      ]. Therefore, providing effective contraception and understanding DDIs between antimicrobials and contraceptives in people living with either HIV or TB are of paramount importance. In the absence of options without concern for DDIs (i.e., copper intrauterine device) or based on patient preference for levonorgestrel EC, double-dose levonorgestrel should be offered to those receiving either efavirenz or rifampicin.

      Implications

      Adjusting levonorgestrel emergency contraception from 1.5mg to 3mg improves levonorgestrel pharmacokinetic exposure in participants receiving either efavirenz-based antiretroviral regimens or rifampicin-containing tuberculosis therapy. These data support guideline recommendations to double the dose of levonorgestrel emergency contraception in persons on medications that decrease levonorgestrel exposure by inducing levonorgestrel metabolism.

      FUNDING

      This work was supported by the National Institute of Allergy and Infectious Diseases [grant number UM1 AI068634, UM1 AI068636 and UM1 AI106701] and the Eunice Kennedy Shrive National Institute of Child Health and Human Development [grant number R01 HD085887 to KS]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
      Role of the funding source: The funders of the study oversaw the development and monitoring of the study, but had no role in the conduct, analyses, and conclusions of the study. CG and PFB-Z, authors of this study and former and current medical officers from NIH/NIAID, had a role in the design, data interpretation, manuscript revision, and intellectual contribution; however, their views were their own and did not represent the funder's views. The corresponding author had full access to all study data and had final responsibility for the decision to submit for publication.

      DATA STATEMENT

      The authors confirm that all data underlying the findings are fully available without restriction. Due to ethical restrictions, study data are available upon request from [email protected] with the written agreement of the AIDS Clinical Trials Group

      DECLARATIONS OF INTEREST

      KKS has received investigator-initiated research support from Organon, LLC, paid to her institution. All other authors report no declarations.

      ACKNOWLEDGEMENTS

      We gratefully acknowledge the patients who participated in this research, and site personnel who contributed to this work, including: Umesh Lalloo and Penelope Madlala, Durban International CRS (Grant UM1AI69432); Patcharaphan Sugandhavesa and Daralak Tavornprasit, Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS, Grant U01AI069399; Hay Mar Su Lwin and Anchalee Avihingsanon, Thai Red Cross AIDS Research Centre (TRC-ARC) CRS, Grant UM1AI69399; Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS; Evans Kachale, Blantyre CRS (Grant 5UM1AI069518); Jaclyn Bennet and Noluthando Mwelase, University of the Witwatersrand Helen Joseph CRS (Grant AI069463, AI068636); Marije Van Schalkwyk and Lynne Cornelissen, Family Clinical Research Unit (FAM-CRU) CRS (Grant 5UM1AI069521); Cecelia Kanyama and Cornelius Munyanga; Malawi CRS (Grant 5UM1AI069423); Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS; Mariam Aziz and Joan A. Swiatek, Rush University CRS (Grant U01 AI069471); Suri Moonsamy and Nazim Akoojee, Soweto ACTG CRS (Grant 5UM1AI069453); Erin Hoffman and Catherine Kronk, Chapel Hill CRS (5UM1AI069423, UL1TR002489); Penn Therapeutics CRS; Unoda A. Chakalisa and Lesedi Tirelo, Gaborone CRS (UM1AI69456); Triniece Pearson and Rachelle Price, Northwestern University CRS (Grant UM1 AI069471, UL1TR001422); Trinity Health and Wellness Center CRS; Jennifer Sullivano and Jamie Nemeth, University of Pittsburgh CRS (UM1AI069494, UL1TR001857); Rebecca Fry and Jessenia Fuentes, Weill Cornell Uptown CRS (Grant UM1 AI069419, UL1 TR002384). In addition, we gratefully acknowledge Karin Klingman for her support during study conduct.

      Appendix. Supplementary materials

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